Pneumocystis has been identified in every mammalian species studied thus far, and genetic analysis has established that each host species harbors a distinct Pneumocystis species. For example, man is the primary host for Pneumocystis jirovecii (Stringer et al., (2002) Emerg. Infect. Dis. 8: 891-896), and the mouse is the primary host of Pneumocystis murina (Redhead et al. (2006) J. Eukaryot. Microbiol.).
Pneumocystis jirovecii is an opportunistic pathogen with a tropism for the alveoli of the lung. The presence of Pneumocystis without clinical signs or symptoms of infection, often referred to as colonization, has been documented in humans. In healthy, immunocompetent individuals, the colonized state tends to be transient. However, in individuals with a weakened immune system, colonization is much more persistent (Morris et al., (2008) J. Infect. Dis. 198: 1345-1352; Nevez et al., (1999) J. Eukaryot. Microbiol.; Morris et al., (2004) Am. J. Respir. Crit. Care Med. 170: 408-413). Subsequently, individuals with weakened immune system have increased susceptibility to Pneumocystis pneumonia (PCP), a fungal infection of the lungs caused by Pneumocystis jirovecii. As the length of survival of HIV, cancer, transplant, and other immunosuppressed patients has increased, so has the prevalence of PCP in the population.
HIV (human immunodeficiency virus) is a viral infection that leads to the progressive failure of the immune system, allowing life-threatening infections and diseases to thrive. In HIV-infected individuals, pulmonary infection with Pneumocystis remains the most common opportunistic infection. Clinically, PCP in HIV-infected individuals is characterized by progressive dyspnea, a non-productive cough or cough productive of clear sputum, malaise and low-grade fever. Prior to highly active anti-retroviral therapy (HAART), PCP was the most common cause of death among HIV-infected individuals. Although HAART has helped control PCP in HIV-infected individuals, there continues to be a significant mortality associated with Pneumocystis infection (Morris et al., (2003) AIDS 17: 73-80; Jain et al., (2003) Clin. Infect. Dis. 36: 1030-1038).
The incidence of PCP in non-HIV individuals has historically been rare; however, the increased clinical use of immunosuppressive and chemotherapeutic agents has resulted in a rise in PCP cases (Sowden et al., (2004) BMC Infect. Dis. 4: 42; De Castro et al. Rev. Mal. Respir. 2007). Those most at risk for PCP include bone marrow transplant patients, solid organ transplant patients, and cancer patients (for example those with hematological malignancies). Others at risk include individuals with collagen vascular disease, inflammatory bowel disease, rheumatoid arthritis and Crohn's disease. Clinical symptoms of PCP in these individuals include fever, dry cough, and shortness of breath, and can quickly progress to respiratory failure.
Pneumocystis infection is generally treated with antimicrobial agents, such as trimethoprim-sulfamethoxazole. Unfortunately, multiple shortcomings have limited the use and effectiveness of these agents. In particular, the incidence of intolerance to these agents is high due to allergies against the sulfa component of the drug. Additionally, long-term use of antimicrobial agents in Pneumocystis-colonized individuals has led to selection for mutations giving rise to drug-resistant strains. Consequently, these shortcomings result in treatment failure and increased mortality (Thomas & Limper, (2007) Nat. Rev. Microbiol. 5: 298-308). Collectively, the increasing incidence of Pneumocystis infection and the shortcomings associated with current Pneumocystis therapies underscore unmet needs for (i) novel primary and adjunctive treatments of infection, and (ii) agents to prevent Pneumocystis infection or the development of Pneumocystis pneumonia. Such a vaccine therapy may serve this dual purpose.